Molecular Mechanism of Epstein-Barr virus DNA replication in viral infected tumors and cellular immunity for viral associated cancers

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EBV encodes seven viral genes that are essential for the oriLyt-dependent DNA replication. The BZLF1 protein is an oriLyt-binding protein and acts also the lytic transactivator. The BALF5 gene encodes the DNA Pol catalytic subunit and the BMRF1 gene encodes the DNA Pol accessory subunit. A single-stranded DNA-binding protein is encoded by the BALF2 gene . The functions of the remaining three proteins encoded by the genes BBLF4 , BSLF1, and BBLF2/3 are not demonstrated but predicted to be helicase, primase, and helicase-primase associated proteins, respectively. In the present study, we found that the EBV DNA Pol catalytic subunit interacts with the BBLF4/BSLF1/BBLF2/3 complex by immunoprecipitation analyses. The interactions of the EBV DNA polymerase with the EBV putative helicase-primase complex warrant particular attention because they are thought to coordinate leading and lagging strand DNA synthesis at the replication fork.We have been also studying cell cycle regulation of latent … More phase EBV DNA replication, focusing on hORC, hCDC6 and hMCM proteins, all of which are thought to be key regulators of initiation of DNA replication. Current model which we hypothesize from our and others data is as follows. ORC and CDC6 are assumed to be associated with the matrix throughout the cell cycle. MCM heterohexameric complexes are loaded, by ORC/CDC6, mainly onto chromatin regions not associated with the matrix. The abundance of chromatin-bound MCM is several times that of bound CDC6, and the relatively large extent of MCM-bound chromatin could explain the pattern of initiation in mammalian cells, namely the so-called "initiation zone". The bound MCMs might be activated through phosphorylation possibly by CDC7 and CDK2 kinase. The activated MCM plays an unknown but essential role in DNA replication, and is simultaneously displaced from chromatin, coupled to DNA replication.Gastric adenocarcinomas carrying EBV are known to be accompanied by massive lymphocyte infiltration. To characterize the tumor infiltrating lymphocytes(TILs), we isolated and cultured such cells from surgically resected EBV-associated gastric carcinoma. The isolated TILs consisted of HLA-class I-restricted CD8+ cytotoxic T lymphocytes(CTLs) which killed autologous EBV-transformed cells but not PHA blast cells and recognized HLA-A24 as restriction molecules. Our data indicated that some cellular proteins may be involved in the strong T cell response to EBV-associated gastric carcinoma. Less